The analysis of foreign particulate matter in orally inhaled and nasal drug products (OINDPs) is an area of recent concern within the pharmaceutical industry. Through various research efforts to include work conducted by the Environmental Protection Agency in development of its air quality standards, particulate matter of very small size has been shown to have the capability to penetrate the deepest parts of the lungs. The EPA has concluded that a link exists between fine particulate matter and numerous health problems including asthma, bronchitis, and various other acute and chronic respiratory symptoms. The pharmaceutical industry has taken it upon itself to conduct various studies to determine the extent to which to foreign particulate matter may have contaminated OINDP products by developing methods of obtaining samples of such products in order to identify and quantify the particulate matter. Foreign particulate matter may originate from a number of sources to include, for example, drug-manufacturing processes, particles found in the inhaler devices that are used to deliver the drug product and others.
Accordingly, a number of techniques are currently used to analyze and enumerate foreign particulate matter in OINDPs. Such techniques may include optical microscopy, SCM/EDX, light obscuration, electrical resistance, and use of a Raman probe. Microscopic techniques offer some advantages in that samples taken allow for collection of both qualitative and quantitative data, i.e., composition and enumeration of the particulate matter found. While obtaining the composition and enumeration of the particulate matter is essential to understanding the potential sources of particulate contamination during product development, such microscopic techniques are laborious and are simply not efficient for routine monitoring of particulate matter. Furthermore, microscopic techniques are inherently subjective and substantial variances in collected data can result. Particulate matter analysis of dry powder inhaler products using microscopy is typically performed by microscopic analysis of insoluble particles collected on a substrate following a filtration of a solution containing the dry powder drug formulation.
Light obscuration techniques generally allow for faster analysis times and larger sample sizes, while removing analysis subjectivity. Additionally, the larger quantity of data obtained through light obscuration techniques can be used to generate statistical evaluation of results over time as part of a stability study. While light obscuration techniques may be known for analysis of foreign particulate matter, there is still a need for methods that optimize efficient and accurate collection of samples so that multiple samples can be obtained at minimum cost and effort.
A number of published articles address the analysis of foreign particulate matter found in dry powder drug products delivered to a user, and these articles specify various collection and analysis techniques. One such article is entitled “Determination of Foreign Particulate Matter in Metered Dose Inhalers (pMDI) by Light Obscuration” (Respiratory Drug Delivery IX, 2004, Pilewski, et al). In this article, light obscuration is used as the method of analysis, and collection of the sample is achieved by multiple actuations of an inhaler device that expels the drug into a diluent held in a trace clean jar. The samples are then filtered and analyzed by light obscuration. The article entitled: “Proposal for Foreign Particles Testing in Orally Inhaled and Nasal Drug Products” (Respiratory Drug Delivery IX, 2004, Hart) discloses various techniques for the analysis of foreign particles to include a comparison of the capabilities and limitations of the various techniques. The article entitled: “Foreign Particles Testing in Orally Inhaled and Nasal Drug Products” (Pharmaceutical Research, Vol. 21, No. 12, December, 2004) provides a summary of industry best practices for testing and controlling foreign particles in OINDPs and provides proposals for developmental characterization and quality control strategies for foreign particles.
While efforts have been made to characterize foreign particulates and to develop various methodologies for sampling and analyzing drugs that have foreign particulate matter, there is still a need for a sampling method and analysis method that allows for faster analysis times, larger sample sizes, while removing as much operator subjectivity as possible without compromising industry accepted standards for conducting such sampling and analysis methods. There is also a need for provision of collection and mixing apparatuses that simplify the methods of sampling and analysis to particularly limit foreign particulate matter from entering a sample that did not originate from the drug as it was packaged and delivered by the recommended inhaler device.